ERS 2022: The Future of Inhalation Therapy in COPD
In this session, experts discussed the novel findings in inhalation therapy in COPD to provide current and future knowledge in the field.
The first talk highlighted the new classes of bronchodilators for treating COPD. Bronchodilator treatment, an essential element in COPD therapy, is still stuck in using beta-2 agonists, muscarinic receptor antagonists, and xanthines. However, a gradual improvement has been observed in these classes of bronchodilators. Currently, there is a scientific and economic interest in using LABA/LAMA FDCs as they induce a synergistic bronchorelaxant effect in human airways, particularly when the medications are combined at isoeffective concentrations. Furthermore, they optimize bronchodilation and are a convenient approach to developing triple therapies that include an ICS. Bidirectional molecular interactions between corticosteroids and beta-2 agonists have been suggested for the reciprocal potentiation of the pharmacological effects of ICS and LABAs. The interaction between a LAMA and an ICS may have anti-remodelling activity in addition to these drugs' well-known bronchodilating and anti-inflammatory activities. In a phase 2a, multicenter, randomized, double-blind, placebo-controlled crossover trial, navafenterol improved lung function, reduced COPD symptoms and decreased objective cough counts to a similar extent to umeclidinium/vilanterol.
Findings from four clinical trials have demonstrated that ensifentrine (RPL554) produced a rapid and significant bronchodilator response in COPD patients, comparable with peak effects reported in such patients with inhaled beta-2 agonists. In addition, Ensifentrine reduced LPS-induced neutrophil and macrophage levels in the sputum of healthy patients, indicating potential anti-inflammatory properties. Three Rho-kinase inhibitors, fasudil, ripasudil, and netarsudil, have been approved in some countries for clinical use but not as bronchodilators. Other novel ROCK inhibitors are under development, including hydroxyfasudil, HA-1152P, AMA0076, and Y-39983. In addition, new classes of bronchodilators are under development for clinical use.
The next talk discussed the beneficial effects of the novel inhaled anti-inflammatory drugs and inhaled monoclonal antibodies. No technology can produce sterilizing immunity in the lung or the nose for any respiratory pathogen. Viral infection drives morbidity and progression and is a significant determinant of colonization and mortality in lung disease. Current vaccine strategies and pharmacotherapy are inadequate. New technologies are being developed that will overcome the limitations of vaccines. To protect the lungs, it is essential to target the nose. Regenerative medicine exploiting lineage commitment biology are now technically feasible.
Treatment of respiratory disease by oral or intravenous delivery may not be very efficient and may require systemic doses that cause side effects. Inhaled medications can be rapidly and noninvasively delivered to the respiratory tract minimizing systemic adverse effects. Inhalation for treating respiratory disease can be the preferred route when a rapid onset of action is required. In 1972, the first inhaled glucocorticoid was available in an MDI. Currently, all national guidelines for COPD recommend an ICS in combination with bronchodilators. Beyond bronchodilation, the search for new drugs for the treatment of COPD remains aimed mainly at finding molecules capable of regulating the inflammatory process. Only a few anti-inflammatory drugs have been tested in humans, and even fewer have been administered by inhalation.
Phosphodiesterase (PDE) inhibitors have been investigated for airway inflammation due to the clinical efficacy of the non-selective PDE inhibitor theophylline. PDE4 inhibitors are an effective therapeutic strategy for inflammatory respiratory diseases as they inhibit the hydrolysis of cyclic adenosine monophosphate (cAMP), effectively increasing levels of cAMP and activating downstream phosphorylation cascades. The dual inhibitor of PDE3 and PDE4, ensifentrine, has been shown to induce significant relaxation of human bronchi in ex-vivo, inducing rapid and sustained bronchodilation in patients with obstructive diseases. Ensifentrine is the only PDE3/PDE4 inhibitor under clinical development for treating asthma, COPD, and cystic fibrosis. A pilot study demonstrated that regular inhaled treatment with heparin-induced clinically significant improvements in lung function and a reduction in air trapping with an improvement in exercise capacity and dyspnea.
Several monoclonal antibodies have been approved for use in severe asthma and are being tested or undergoing clinical evaluation for COPD treatment. However, technological issues like stability during the administration of monoclonal antibodies complicate inhalation use. Therefore, it is not yet possible to predict which new inhaled drug will be introduced for COPD. Nevertheless, the ongoing efforts to provide physicians and patients with new effective molecules are tangible. However, it should be emphasized that the developing of new inhaled drugs for use in COPD should be accelerated.
The next talk discussed the evolution of pulmonary drug delivery devices in respiratory disorders. Pulmonary drug delivery devices have evolved for many years. Inhalation is an effective route for the treatment of the majority of respiratory disorders. It targets drugs directly to the lungs. Compared to systemic routes, a smaller drug dose can be used, the onset of action is rapid, and the incidence of side effects is less. Particle size influences total lung deposition and the regional site of airway drug deposition. In asthma patients, using smaller particles led to better total lung deposition and greater penetration of that aerosol into the lung. In COPD, too, smaller particles achieved better total lung deposition and distribution throughout the airway. For drug delivery to the lower respiratory tract and lungs, particle size can be acceptable (2-5 µm) or extra fine (< µ2 m), which influences the total respirable fraction (particle < µ5 m) and the amount and site of drug deposition (more peripheral deposition with extra fine particles). New propellants have also evolved in formulations. In 2020, two companies announced pMDIs with low-global warming potential (GWP) propellant for 2025. Using the myAirCoach mHealth-supported self-management system improves asthma control and quality of life, reducing severe asthma exacerbations. To achieve adequate drug delivery, the science of aerosol formulations, device engineering, patient technique and training is required.
European Respiratory Society (ERS) International Congress 2022, 3rd-6th Sept. 2022, Barcelona
